chr22-18925165-A-T

Variant names:

• chr22-18925165-A-T
• rs4819756
• NM_016335.6:c.553T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016335.6(PRODH):​c.553T>A​(p.Trp185Arg) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W185Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83
• Publications: 48 publications found

Genes affected

PRODH (HGNC:9453): (proline dehydrogenase 1) This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 and susceptibility to schizophrenia 4 (SCZD4). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2010]

PRODH Gene-Disease associations (from GenCC):

• hyperprolinemia type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08179915).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016335.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	NM_016335.6	MANE Select	c.553T>A	p.Trp185Arg	missense	Exon 4 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.229T>A	p.Trp77Arg	missense	Exon 4 of 14	NP_001182155.2
	PRODH	NM_001368250.2		c.229T>A	p.Trp77Arg	missense	Exon 4 of 14	NP_001355179.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.553T>A	p.Trp185Arg	missense	Exon 4 of 14	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.553T>A	p.Trp185Arg	missense	Exon 5 of 15	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.229T>A	p.Trp77Arg	missense	Exon 4 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.039
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.2
DANN	Benign	0.24
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.91
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.0069	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.89	T
PhyloP100		3.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	3.7	N
REVEL	Benign	0.13
Sift	Benign	0.50	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.033
MutPred		0.32		Gain of disorder (P = 0.0017)
MVP		0.35
MPC		0.48
ClinPred		0.067	T
GERP RS		2.9
gMVP		0.36
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4819756; hg19: chr22-18912678;